Zirconium bis(pyridonate): A modified amidate complex for enhanced substrate scope in aminoalkene cyclohydroamination

Article abstract of DOI:10.1039/b913393c

A new bis(amidate)zirconium bis(amido) hydroamination pre-catalyst using 6-tert-butyl-3-phenyl-2-pyridone as a proligand has been prepared and characterized. This rare example of an early transition metal complex incorporating a 2-pyridonate derivative as an ancillary ligand was found to be effective for the cyclohydroamination of aminoalkenes, including more challenging substrates bearing unactivated internal CC bonds. The Royal Society of Chemistry.

Full text of DOI:10.1039/b913393c

View Article Online / Journal Homepage / Table of Contents for this issue
This article is published as part of the Dalton Transactions themed issue entitled:
New Talent
Showcasing the strength of research being carried out by
tomorrow's leaders in the field of inorganic chemistry
Guest Editor Polly Arnold
University of Edinburgh, UK
Published in issue 2, 2010 of Dalton Transactions
Image reproduced with permission of Mark Muldoon
Articles in the issue include:
PERSPECTIVES:
Modern multiphase catalysis: new developments in the separation of homogeneous catalysts
Mark J. Muldoon, Dalton Trans., 2010, DOI: 10.1039/b916861n
Probing bioinorganic chemistry processes in the bloodstream to gain new insights into the origin of
human diseases
Elham Zeini Jahromi and Jürgen Gailer, Dalton Trans., 2010, DOI: 10.1039/b912941n
COMMUNICATIONS:
Facile entry to 3d late transition metal boryl complexes
Ba L. Tran, Debashis Adhikari, Hongjun Fan, Maren Pink and Daniel J. Mindiola,
Dalton Trans., 2010, DOI: 10.1039/b912040h
Probing the kinetics of ligand exchange on colloidal gold nanoparticles by surface-enhanced raman
scattering
Yuhua Feng, Shuangxi Xing, Jun Xu, Hong Wang, Jun Wei Lim and Hongyu Chen,
Dalton Trans., 2010, DOI: 10.1039/b912317b
Visit the Dalton Transactions website for more cutting-edge inorganic and organometallic research
www.rsc.org/dalton

COMMUNICATION
www.rsc.org/dalton | Dalton Transactions
Zirconium bis(pyridonate): a modified amidate complex for enhanced
substrate scope in aminoalkene cyclohydroamination†
Jason A. Bexrud and Laurel L. Schafer*
Received 6th July 2009, Accepted 29th September 2009
First published as an Advance Article on the web 12th October 2009
DOI: 10.1039/b913393c
A new bis(amidate)zirconium bis(amido) hydroamination
pre-catalyst using 6-tert-butyl-3-phenyl-2-pyridone as a proli-
gand has been prepared and characterized. This rare example
of an early transition metal complex incorporating a 2-
pyridonate derivative as an ancillary ligand was found to
be effective for the cyclohydroamination of aminoalkenes,
including more challenging substrates bearing unactivated
observed with our previously reported amidate catalyst systems
is that the large steric bulk associated with these ligands, though
advantageous for minimizing the in situ formation of catalytically
inactive imido dimers,6d may be impeding these more sterically
demanding intramolecular aminoalkene reactions.
To improve steric accessibility, 2-pyridonate derivatives were
used as a new catalyst motif, as the substituents of 2-pyridonates
are more removed from the metal center in comparison to the
substituents of the amidate ligands (Fig. 1).
=
internal C C bonds.
Nitrogen containing compounds are ubiquitous in chemistry
and are important for the agrochemical, pharmaceutical, and
fine chemical industries. Therefore, the development of new
methodologies that have the potential to reduce cost, simplify
production and reduce the environmental impact of their syntheses
is important. To this end, hydroamination has drawn a great deal
of attention in past years,1–3 as a desirable catalytic technology for
the synthesis of amines and N-containing heterocycles. Despite
over 15 years of intense investigation, a robust, reactive, selective,
and functional group tolerant catalyst system for use with a broad
range of unactivated alkene substrates remains an elusive goal.
Here, we report a modular bis(pyridonate)zirconium pre-catalyst
for the hydroamination of aminoalkene substrates with improved
substrate scope, including the first example of diastereoselective
cis-fused octahydroindole ring formation.
Fig. 1 Steric relationship between amidate and pyridonate ligands.
Such 3,6-disubstituted pyridone proligands can be prepared
in good yield in a two-step reaction, which uses commercially
available terminal alkyne and aldehyde starting materials.8 Fur-
thermore, these ligands are anticipated to be more electron-
withdrawing than their conventional amidate counterparts (based
upon the respective pKa values of the proligands),9 and could
therefore serve as a means of generating a more electrophilic and
reactive metal center.10
Group four based organometallic complexes have played a
prominent role in the field of hydroamination catalysis, due to
their low cost, low toxicity, and high reactivity.4–6 Recent reports
highlighting the increasingly efficient and diverse capability of
these catalytic systems have shown that alkynes,4 allenes,5 and
alkenes6 can be converted to imines, amines and N-heterocycles
with a high degree of regio- and stereoselectivity. However, the air
and water sensitivity of these complexes coupled with substrate
scope limitations, have hindered their application in organic
synthesis.
While there are numerous examples of transition metal com-
plexes employing the pyridonate ligand motif,11 only a few
monomeric early transition metal 2-pyridonate complexes are
known, such as pentamethylcyclopentadienyl (Cp*) Zr and Ti
2
pyridonate complexes (Cp*Zr(k -O,N-6-methyl-2-pyridonate)3,12
1
Cp*TiMe(h -O-3-cyano-4,6-dimethyl-2-pyridonate)2.13 Most im-
portantly, none of these previously reported complexes have been
used for catalysis.
Here, the 6-tert-butyl-3-phenyl-2-pyridone proligand was pre-
pared as
a
crystalline solid (Scheme 1).8 With this in
To date, the work carried out in the Schafer group has
focused on the use of bis(amidate) bis(amido) complexes of
titanium and zirconium as hydroamination pre-catalysts.7 Thus
hand, the related bis(2-pyridonate) zirconium bis(dimethylamido)
=
far, aminoalkene substrates bearing unactivated internal C C
bonds have been challenging transformations for this class of
catalysts.6a,f One explanation for the moderate to poor reactivity
Department of Chemistry, University of British Columbia, Vancouver, British
Columbia, Canada.2036 Main Mall, Vancouver, British Columbia, Canada
V6T 1Z1. E-mail: schafer@chem.ubc.ca
† Electronic supplementary information (ESI) available: Experimental
procedures, NMR spectra as well as a CIF file giving X-ray crystallo-
graphic data for complex 1. CCDC reference number 747413. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b913393c
Scheme 1 Synthesis of 6-tert-butyl-3-phenyl-2-pyridone proligand.8
Dalton Trans., 2010, 39, 361–363 | 361
This journal is
The Royal Society of Chemistry 2010
©

Table 1 Catalytic cyclohydroamination results
complex 1 can be prepared using a high yielding protonolysis
reaction (eqn (1)) to give microcrystalline crude material. Recrys-
tallization of complex 1 from a benzene–pentane mixture gives
crystals suitable for crystallographic analysis. In the solid state,
1 is mononuclear, and possesses a distorted octahedral geometry
about the metal center with the 6-tert-butyl-3-phenyl-2-pyridonate
ligands adopting a bidentate binding motif (Fig. 2).
Entry
1
Aminoalkene
t/h
T/◦C
Yield a(%)
5
110
>98
2
3
4
5
96
5
110
110
110
110
87
(1)
>98
43
96
96
This complex assumes an O-trans C2 coordination geometry
with the dimethylamido ligands positioned cis to one another.
The binding of the 2-pyridonate oxygen and nitrogen donors
is best described as an alkoxyimine bonding motif, as can be
35
seen by the substantially different Zr–O/Zr–N bond lengths
1
(2.095(1)/2.440(2) A). The H and 13C NMR spectra and variable
6
7
168
168
145
145
59
˚
temperature NMR experiments (from 100 ◦C to -100 ◦C) suggest
that this complex maintains a C2 symmetric geometry in solution,
consistent with the solid state molecular structure and no fluxional
behaviour is observed. Results of NOE spectroscopic investiga-
tions show that the methyl groups of the amido ligands and the
t-butyl groups of the 6-tert-butyl-3-phenyl-2-pyridonato ligands
are located in close proximity to one another, as they would be in
52b
a Yield determined by NMR spectroscopy using 1,3,5-trimethoxybenzene
as an internal standard. b Isolated yield following conversion to the N-Ts
derivative.
2
a k bound arrangement. In addition, an NOE contact was also
found between the t-butyl group and the phenyl group of the 6-tert-
butyl-3-phenyl-2-pyridonate ligand. Again, the close proximity of
these groups on adjacent ligands supports the assignment of a
k -N,O bound coordination geometry. This complex is thermally
robust but is air and moisture sensitive.
2-methyl-4,4-diphenylpyrrolidine within five hours at 110 ◦C. Both
5 and 6 membered rings can be accessed (entries 2 and 3) and
importantly, an activated internal alkene can be used (entry 4).
Overall, this system exhibits an acceptable level of reactivity with
yields and reaction times that are comparable to those obtained
using previously reported zirconium catalyst systems.6 Efforts
to mediate the cyclohydroamination reaction with secondary
amines were not successful, suggesting that complex 1 mediates
cyclohydroamination via an intermediate Zr imido complex, as has
been previously proposed for several Zr hydroamination catalyst
systems.6a,d,e,f,14 Entry 5 shows that for complex 1, substrates do
not require the gem-disubstituent effect to achieve the desired
reactivity. Here, diastereoselectivity of greater than 10 : 1 in favour
of the trans 2,5-dimethylpyrrolidine product can be observed,
which is consistent with a preference for the a-methyl group to
be in an equatorial position in the proposed chair-like transition
state (Scheme 2).6
2
Fig.
2
ORTEP diagram of the solid-state molecular structure
of bis(6-tert-butyl-3-phenyl-2-pyridonato)zirconium bis(dimethylamido)
complex 1. Hydrogen atoms have been omitted for clarity. Thermal
ellipsoids are drawn at the◦50% probability level. Selected average bond
˚
distances (A) and angles ( ): Zr(1)–N(1,2) = 2.440(2), Zr(1)–N(3,4) =
2.028(2), Zr(1)–O(1,2) = 2.095(1), N(1,2)–Zr(1)–N(4,3) = 146.24(6),
O(1)–Zr(1)–O(2) = 157.34(5), O(1,2)–Zr(1)–N(1,2) = 58.10(5).
Scheme 2 Chair-like transition state for the diastereoselective formation
of trans 2,5-dimethylpyrrolidine.
Complex 1 was first tested for aminoalkene hydroamination
activity using the standard geminally disubstituted test sub-
strate 2,2-diphenyl-4-pentenylamine (entry 1, Table 1).6 Com-
plex 1 catalyzes this transformation, with complete conversion to
Previous to this work, no group four pre-catalysts had been
reported for the cyclohydroamination of unactivated internal
alkenes, such as 2,2-diphenyl-4-hexenylamine (entry 6). However,
362 | Dalton Trans., 2010, 39, 361–363
This journal is
The Royal Society of Chemistry 2010
©

this substrate does indeed undergo cyclohydroamination in the
presence of complex 1 at elevated temperature.
M. J. Molski, A. Luhl, P. W. Roesky, M. Dochnahl and S. Blechert,
Eur. J. Inorg. Chem., 2009, 1369; (d) P. Horrillo-Martinez and K. C.
Hultzsch, Tetrahedron Lett., 2009, 50, 2054; (e) K. D. Hesp and M.
Stradiotto, Org. Lett., 2009, 11, 1449; (f) A. G. M. Barrett, I. J. Casely,
M. R. Crimmin, M. S. Hill, J. R. Lachs, M. F. Mahon and P. A.
Procopiou, Inorg. Chem., 2009, 48, 4445; (g) G. Zi, Q. Wang, L. Xiang
and H. Song, Dalton Trans., 2008, 5930; (h) J. R. Zhou and J. F. Hartwig,
J. Am. Chem. Soc., 2008, 130, 12220; (i) C. Quinet, P. Jourdain, C.
Hermans, A. Ates, I. Lucas and I. E. Marko´, Tetrahedron, 2008, 64,
1077; (j) C. Munro-Leighton, S. A. Delp, N. M. Alsop, E. D. Blue and
T. B. Gunnoe, Chem. Commun., 2008, 111.
3 Selected recent references for group 4 metals include: (a) G. F. Zi, X.
Liu, L. Xiang and H. B. Song, Organometallics, 2009, 28, 1127; (b) K.
Weitershaus, B. D. Ward, R. Kubiak, C. Muller, H. Wadepohl, S. Doye
and L. H. Gade, Dalton Trans., 2009, 4586; (c) B. Lian, T. P. Spaniol, P.
Horrillo-Martinez, K. C. Hultzsch and J. Okuda, Eur. J. Inorg. Chem.,
2009, 429; (d) S. Majumder and A. L. Odom, Organometallics, 2008, 27,
1174; (e) H. Kim, T. Livinghouse and P. H. Lee, Tetrahedron, 2008, 64,
2525; (f) C. Muller, W. G. Saak and S. Doye, Eur. J. Org. Chem., 2008,
2731; (g) N. Vujkovic, B. D. Ward, A. Maisse-Francois, H. Wadepohl,
P. Mountford and L. H. Gade, Organometallics, 2007, 26, 5522.
4 (a) Z. Zhang, D. C. Leitch, M. Lu, B. O. Patrick and L. L. Schafer,
Chem.–Eur. J., 2007, 13, 2012; (b) N. Schwarz, K. Alex, I. A. Sayyed,
V. Khedkar, A. Tillack and M. Beller, Synlett, 2007, 1091; (c) A. L.
Odom, Dalton Trans., 2005, 225; (d) M. A. Esteruelas, M. A. Lopez,
A. C. Mateo and E. Onate, Organometallics, 2005, 24, 5084; (e) Y. Li,
Y. Shi and A. L. Odom, J. Am. Chem. Soc., 2004, 126, 1794; (f) A.
Heutling, F. Pohlki and S. Doye, Chem.–Eur. J., 2004, 10, 3059; (g) F.
Pohlki and S. Doye, Chem. Soc. Rev., 2003, 32, 104.
As a demonstration of the potential value of this reactivity, the
cyclization of 2-(cyclohex-2-enyl)-2,2-diphenylethylamine can also
be performed at elevated temperature with moderate yield and
very high selectivity for the cis-fused octahydroindole (entry 7).
This reaction demonstrates the potential of this methodology for
the generation of biologically relevant fused-polycyclic structural
motifs found in numerous alkaloids including strichnine.15
Due to the improved substrate scope observed here, we fur-
ther challenged the system with the formation of larger seven-
membered azapane cyclohydroamination products. Thus, 2,2-
diphenyl-6-heptenylamine was examined as a substrate (eqn (2))
and it was found that 2-methyl-6,6-diphenylazepane is formed in
low yield (28%) due to the preferential formation of 2,2-diphenyl-
6-methylcyclohexylamine via an intramolecular hydroaminoalky-
lation reaction pathway.16
The formation of the new C–C bond in the major product
is thought to be produced by an alternate mechanistic pathway
involving C–H bond activation and has been previously reported
by ourselves and others.16,17
5 (a) R. O. Ayinla and L. L. Schafer, Inorg. Chim. Acta, 2006, 359,
3097; (b) J. M. Hoover, J. R. Petersen, J. H. Pikul and A. R. Johnson,
Organometallics, 2004, 23, 4614; (c) J. S. Johnson and R. G. Bergman,
J. Am. Chem. Soc., 2001, 123, 2923.
(2)
6 (a) M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak and L. L.
Schafer, Angew. Chem., Int. Ed., 2007, 46, 354; (b) A. L. Gott, A. J.
Clarke, G. J. Clarkson and P. Scott, Organometallics, 2007, 26, 1729;
(c) C. Muller, C. Loos, N. Schulenburg and S. Doye, Eur. J. Org.
Chem., 2006, 2499; (d) R. K. Thomson, J. A. Bexrud and L. L. Schafer,
Organometallics, 2006, 25, 4069; (e) D. A. Watson, M. Chiu and R. G.
Bergman, Organometallics, 2006, 25, 4731; (f) H. Kim, Y. K. K. Kim,
J. H. Shim, M. Kim, M. Han, T. Livinghouse and P. H. Lee, Adv.
Synth. Catal., 2006, 348, 2609; (g) L. T. Kaspar, B. Fingerhut and L.
Ackermann, Angew. Chem., Int. Ed., 2005, 44, 5972.
In conclusion, we have reported the synthesis and characteri-
zation of the first bis(pyridonate) zirconium bis(amido) complex.
This compound was found to display an improved scope of reac-
tivity for group 4 catalyzed cyclohydroamination. We suggest that
the greater accessibility of the reactive metal center afforded by
the 6-tert-butyl-3-phenyl-2-pyridonate ancillary ligand allows for
the successful cyclization of more sterically demanding substrates.
The enhanced electrophilicity of the metal center, due to the
incorporation of electron-withdrawing ligands, results in enhanced
reactivity trends. Future work will involve further modification of
this flexible proligand to improve reactivity and selectivity for both
hydroamination and hydroaminoalkylation reactions.
7 A. V. Lee; and L. L. Schafer, Eur. J. Inorg. Chem., 2007, 2245.
8 L. E. Overmann, S. Tsuboi, J. P. Roos and G. F. Taylor, J. Am. Chem.
Soc., 1980, 102, 747.
9 F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456.
10 (a) J. A. Bexrud, C. Li and L. L. Schafer, Organometallics, 2007, 26,
6366; (b) A. V. Lee and L. L. Schafer, Organometallics, 2006, 25,
5249.
11 (a) S. M. Kuang, P. E. Fanwick and R. A. Walton, J. Chem. Soc., Dalton
Trans., 2002, 2501; (b) T. C. Flood, J. K. Lim and M. A. Deming,
Organometallics, 2000, 19, 2310; (c) S. Parsons and R. E. P. Winpenny,
Acc. Chem. Res., 1997, 30, 89; (d) J. M. Rawson and R. E. P. Winpenny,
Coord. Chem. Rev., 1995, 139, 313.
12 A. Antinolo, F. Carrillo-Hermosilla, A. E. Corrochano, R. Fandos,
J. Fernandez-Baeza, A. M. Rodry´guez, M. J. Ruiz and A. Otero,
Organometallics, 1999, 18, 5219.
13 R. Fandos, C. Hernandez, A. Otero, A. M. Rodry´guez, M. J. Ruiz and
P. Terreros, Eur. J. Inorg. Chem., 2003, 493.
14 A. L. Gott, A. J. Clarke, G. J. Clarkson and P. Scott, Chem. Commun.,
2008, 1422.
Acknowledgements
The authors thank the NSERC (graduate fellowship to JAB and
discovery grant to LLS), and Boehringer Ingelheim Canada Ltd.
for financial support. We thank Brian O. Patrick and Robert K.
Thomson for X-ray crystallographic assistance. LLS is an Alfred
P. Sloan Fellow.
15 R. Lebeuf, F. Robert, K. Schenk and Y. Landais, Org. Lett., 2006, 8,
References
4755.
16 (a) J. A. Bexrud, P. Eisenberger, D. C. Leitch, P. R. Payne and L. L.
Schafer, J. Am. Chem. Soc., 2009, 131, 2116; (b) S. B. Herzon and J.F.
Hartwig, J. Am. Chem. Soc., 2008, 130, 14940–14941.
17 R. Kubiak, I. Prochnow and S. Doye, Angew. Chem., Int. Ed., 2009, 48,
1153.
1 For recent review see: T. E. Muller, K. C. Hultzsch, M. Yus, F. Foubelo
and M. Tada, Chem. Rev., 2008, 108, 3795.
2 Selected recent references for non-group 4 metals include: (a) H. F. Yuen
and T. J. Marks, Organometallics, 2009, 28, 2423; (b) H. Ohmiya, T.
Moriya and M. Sawamura, Org. Lett., 2009, 11, 2145; (c) K. Lohnwitz,
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 361–363 | 363
©